Food Allergy and Food Intolerance: Specific Versus Innate Immunity Roger Davis Deutsch

The Original Internist article Food Allergy and Food Intolerance: specific versus innate immunity Roger Davis Deutsch Nomenclature The concept of an allergy was fairly well understood when von Pirquet, an Austrian physician, first introduced the term in 1906. It was intended to denote an altered reaction to a normally innocuous substance. Two decades later allergists in Europe agreed to narrow the definition to apply only to such an altered reaction as may be characterized by an immediate onset of symptoms. Contemporary physicians recognize a distinction between immediate and delayed-type altered reactions in their nomenclature by applying the terms, “intolerance” or “sensitivity” in the case of common reactions to foods and other chemicals, where symptom onset is delayed and typically of a less acute nature than that which has come to be known as a “true” allergy, classical allergy, or Type I hypersensitivity, according to the Gell and Coombs classification system. Although both phenomena involve an aberrant immune response, the mechanisms underlying each are quite different. Broadly speaking, classical allergy is a function of the specific immune system, whilst intolerance involves activation of the innate branch of the immune system. Classical allergy is a function of the specific immune system The most prominent hallmark of specific immunity is memory; hence the rationale underlying immunization. It is termed, “specific” because it makes use of pathogen- or allergen-specific binding sites on Immunoglobulins or lymphocyte receptor molecules in the process of recognition. Prior exposure to the activating substance is therefore necessary in order to “prime” or elicit a subsequent response of the specific immune system. Lymphocytes that initiate an allergic response first manufacture antibodies specific to the particular allergen. Although the European allergists where unaware of the causative agent, experimentation performed by allergists Praustnitz and Kustner in 1920 demonstrated that passive transfer of allergy could occur by injecting the serum of an allergic subject into the tissue of a non-allergic recipient. Subsequent scratch testing at the site with the specific allergen induced a classical wheal and flare reaction. Although the causative factor existing in the serum was unknown, it was referred to it as regain. 1 IgE In 1967 two independent teams discovered that the reaginic antibody (regain) was IgE. One was a husband and wife team in Colorado, named, Ishizaka; the other a three member team at the Karolinska Institute in Sweden. The Karolinska team later developed an immunoassay for quantitation of allergen specific IgE. The test is called RAST, an acronym for Radio Allergo Sorbent Test. It is a sandwich immunoassay using a radiolabled anti-IgE antibody tag. When radiation emitted from cloned antibodies bound to the allergen specific IgE antibodies is measured it provides a reliable indication of allergy. Variations of the technique using enzyme tags and optical densitometric readings (ELISA) are commonly used. The role of IgE in the pathogenesis of allergy was later elucidated. Essentially, an antigen capturing and presenting cell (usually a macrophage or dendritic cell) takes up an allergen and then breaks it down internally. The broken down peptides of the allergen bind to a major histocompatibility complex molecule (MHC molecule) and the MHC/allergen complex then migrates to the surface membrane. A T-cell, in this case a T-Helper 2 cell with a conforming receptor molecule, will recognize the antigen peptide/MHC complex. Once the required interaction, i.e., binding of the allergen particles/MHC complex with the T-cell receptor; and, a co-stimulatory signal, usually involving a B7 molecule on the APC and a CD 28 receptor on the T-cell, occurs, the T- cell becomes activated. It then “instructs” contacted B-lymphocytes with a conforming receptor to also become active. In this allergic pathway the chemical message is Interleukin 4 (IL4). The so activated B- cells transform into plasmacytes, commence manufacturing antibodies specific to the allergen peptides in question, multiply, and secrete soluble forms of the specific receptor molecule, in other words, allergen specific IgE antibodies conforming with the original allergen peptides, into the lymph and general circulation. Once in circulation IgE antibodies will bind with fc receptors on the surfaces of mast cells occurring in the connective tissue of the skin, as well as other mucosal linings, and basophils in the blood. These white blood cells possess internal granules containing pre- formed mediators of inflammation, including histamine. Should two or more cell-bound IgE antibodies subsequently encounter the specific allergen, their binding and “cross- linking” causes aggregation of cell membrane receptors inducing various enzymes and kinases to initiate a process resulting in the release of these mediators. The process is known as degranulation, (figure 1) and will rapidly induce an inflammatory response; giving rise to increased blood vessel permeability, mucus secretion, irritation of nerve endings and smooth muscle constriction, all common traits of “true” allergy. In addition to the release of pre-formed mediators, of which histamine is most common, the cells will also synthesize lipid mediators known as prostaglandins and leucotrienes, 2 which augment and prolong the reaction. Some lipid mediators can exert a constrictive effect on smooth muscles surrounding the bronchial tube which is 30 times more powerful than that of histamine. The substrates of these lipid mediators derive from ω6 fats and thus dietary emphasis on the ω3’s, which will compete for the common enzymatic pathway, represents a sound dietary strategy for curbing inflammation. Both pre-formed and newly synthesized lipid mediators, as well as other cytokines, like IL3, 5 and granulocyte macrophage-colony stimulating factor, will attract other inflammatory white cells -basophils and eosinophils, but not nutrophils- to the local site of the reaction, causing further and prolonged damage to the tissue. A chronic state of inflammation and allergic lesions may ensue. Although nutrohils are not directly involved in Type one allergy, as we’ll see, they are the cells most involved in intolerance. It is also worth noting that this pathway not only depends on the binding of the cell bound IgE antibodies and the specific allergen, but also on a secondary or co-stimulatory signal generated by the antigen presenting cell. In fact, in the absence of this secondary signal the T-cell will actually become anergic. In fact, this is the mechanism by which T-cells develop tolerance to self proteins whilst they are maturing in the thymus. Therefore, clinicians should be circumspect regarding claims that an in vitro lab test will detect either allergy, or intolerance, when a specific condition of the assay calls for the isolation of the lymphocytes in autologous serum, because; by definition, the antigen presenting cells and the necessary co-stimulatory signal they provide, are absent. Cellular Degranulation Reaction (inducing mediator release) (Fig. 1) 3 IgE associated with parasitic infection: IgG associated with smaller micro-organisms (bacterial and viral) Since IgE is instrumental in this process, a therapeutic strategy of injecting antibodies targeted against the cell binding portion of the IgE molecules appear to block the interaction at a critical point and thus prevents mast cell and basophil activation. In some test subjects, allergic subjects appear to have achieved tolerance to peanut under experimental conditions. However, there can be an untoward side effect of down regulating IgE. This T-Helper 2 pathway is activated by parasitic infections. The resulting explosive release of toxic inflammatory mediators, such as histamine, is a logical strategy for the immune system when confronting a pathogen of such relatively large size. Thus, indiscriminately blocking the IgE mechanism may render the organism more susceptible to parasitic infection. Modulation of the specific immune response to prevent allergy Fortunately, a subtler and more specific therapy has been researched which, theoretically, will block a specific allergen reaction while leaving the general protective function of the immune system intact. This more recent and promising approach to classical allergy lies with redirecting or modulation of this pathway to the non allergy provoking T Helper 1 pathway. When the immune system is confronted with a virus or bacteria instead of a parasite, the same basic series of events occur, except that T Helper 1, as opposed to TH 2 cells, are activated, and the signals they transmit to B cells, notably, interferon γ (as opposed to IL 4) induce the B cells to produce antibodies of the IgG isotype, rather than the pathogenic IgE isotype. Instead of binding to mast cells and basophils and inducing them to release their deadly chemical arsenals, IgG antibodies, which are about 10,000 times more prevelant than IgE, will coat the virus or bacteria, thus enabling a phagocyte to dock onto it and degrade it, with the help of lysosomal enzymes. Whereas this process is effective against infection, it does not, notably, produce symptoms of allergy. This therapeutic effect is achieved by the use of injections of “immunostimulatory sequences” (ISS) of bacterial or viral nucleotides, covalently bound to the specific antigenic epitope. The bacterial or viral nucleotides will attract a TH1 cell rather than the TH2

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